Saturday, February 02, 2013

Should Expected Clinical Outcomes of the Disease under Study, which are study endpoints, be reported as AEs/SAEs?

Generally not. The new IND safety reporting
regulation and associated guidance state that study endpoints that are Serious Adverse Events (SAEs) (i.e., the study is evaluating whether the Investigational Medicinal Products reduces the rate of the SAE) do
not require immediate reporting to the sponsor unless there is evidence
suggesting a causal relationship between the drug and the event. For example, a
death ordinarily would not require immediate reporting to the sponsor as an SAE
under a trial designed to compare all-cause mortality in subjects receiving
either drug treatment or a placebo. On the other hand, in the same trial with
an all-cause mortality endpoint, if the death occurred as a result of an
anaphylactic reaction that coincided with initial exposure to the drug, or as a
result of fatal hepatic necrosis, the death must be immediately reported to the
sponsor as a SAE

Study endpoint information
should be collected, tracked, and monitored, usually by a data monitoring
committee, during the course of the study. The sponsor must report study
endpoints to the FDA according to the protocol and not as IND safety reports, except in unusual cases
as described above.

Some protocols instruct
investigators to record and report all untoward events that occur during a
study as AEs/SAEs, which could include common symptoms of the disease under
study and/or other expected clinical outcomes that are not study endpoints.
This approach enables frequency comparisons of all events between treatment
groups, but can make event recording in the CRF burdensome, result in more
expedited reports from investigators to sponsor, and fill safety databases with
many untoward events that most likely have no relationship to study treatment
and that could obscure signal identification.

In practice, some companies
take the conservative approach and report the underlying disease symptoms /
outcomes as the adverse events or serious adverse events. To report all underlying disease symptoms / outcomes as
adverse events is overkill and the symptom worsening could just be the
lack of efficacy for the study drug. It may be reasonable not to report the
underlying disease symptoms / outcomes as adverse events, but if the underlying disease symptoms / outcomes result in the consequences that meet the criteria
for serious adverse event (see
the SAE criteria in ICH E2D or EMA
document ICH topic E2 A), the underlying disease symptoms / outcomes should
be reported as AE and SAE. This seems to be the approach that a lot of
pharmaceutical companies are taking.

In a clinical trial with tiotropoim
in COPD patients, Boehringer-Ingelheim reported the most commonly serious
adverse events as the following:

“COPD exacerbations were
the most commonly reported serious adverse events. The incidence of COPD
exacerbations reported as SAEs was lower in the Tiotropium group compared to
placebo group (4.2% vs. 6.7% of patients, respectively).”

COPD exacerbation is
underlying disease symptom and efficacy measure of the COPD, but if COPD
exacerbation requires the hospitalization (also meet the severe exacerbation
definition), the COPD exacerbation would need to be reported as SAE even though
the mild / moderate COPD exacerbation may not be reported as adverse event.

For a clinical trial with
thrombolytic agents such as tPA, any bleeding event should be reported as AE.
However, in trials in Hemophilia patients, the bleeding event is the
manifestation for the underlying disease (hemophilia A). The bleed event should not be reported
as AE unless it meet the SAE criteria in which case, the bleeding event should
be reported as SAE. Bleeding would also
be included in the efficacy assessment. It
would be appropriate to specify in the study protocol what should be and what
should not be reported. The following language would be adequate in Hemophilia
trials.

“Spontaneous and
trauma-related bleeding episodes are expected as usual events in subjects with
severe Hemophilia A. Thus, bleeding episodes need not be reported as adverse
events unless severe enough to be classified as a serious adverse events. “

The worst situation is
that the rule for reporting is not explicitly specified in the study protocol
and different investigational sites take different approaches (at investigator’s
discretion) in reporting the AE/SAE for underline disease symptoms / outcomes.
In this situation, data are inconsistent across different sites.

1 comment:

maggie.danhakl@healthline.com
said...

Hi Dr. Deng,

I hope all is well with you. Healthline just published an infographic detailing the effects of anaphylaxis on the body. This is an interactive chart allowing the reader to pick the side effect they want to learn more about.

You can see the overview of the report here: http://www.healthline.com/health/anaphylaxis/effects-on-body

Our users have found our guide very useful and I thought it would be a great resource for your page: http://onbiostatistics.blogspot.com/2013/02/should-expected-clinical-outcomes-of.html

I would appreciate it if you could review our request and consider adding this visual representation of the effects of anaphylaxis to your site or sharing it on your social media feeds.